PROJECT SUMMARY: An emerging paradigm suggests that gut glycosylation is a key force in maintaining a homeostatic relationship between the gut and its microbiota. Nevertheless, it is unclear how host glycosylation machinery contributes to HIV-associated microbial translocation and inflammation. Our published data show that the host circulating glycome is altered in HIV+ individuals, and that these changes persist despite antiretroviral therapy (ART). In particular, we observe a persistent HIV-associated loss of sialic acid (hypo-sialylation) from plasma glycoproteins. This suggested to us that HIV infection may also be associated with glycomic alterations in other body compartments, including the gut. We therefore used ileum and sigmoid colon biopsies from 20 HIV+ ART-suppressed individuals and found that gut glycomic patterns are indeed associated with distinct microbial compositions, markers of inflammation, and HIV persistence. In particular, we found that: (1) Increased levels of mucosal-associated, hypo-sialylated O glycans correlated with a dysbiotic and less diverse gut microbiome, higher plasma levels of inflammatory markers, and higher levels of ileum-associated HIV DNA. These data are intriguing because non-HIV studies show that sialic acid catabolism (removal, via sialidase) drives microbial dysbiosis/translocation and intestinal inflammation. (2) Increased levels of fucosylated glycans correlated with higher microbiome diversity, lower dysbiosis, and lower inflammation. These correlations are consistent with reports, in the general population, that gut fucosylation sustains host-commensal symbiosis and prevents gut inflammation by suppressing bacterial virulence genes. We hypothesize that HIV infection causes persistent gut glycomic alterations ? mainly hypo-sialylation and lack of proper fucosylation (dys-fucosylation) ? that alter microbiome composition, leading to microbial translocation, inflammation, and HIV persistence. In Aim 1A, we will determine the impact of SIV infection on the gut glycome and the effects of this impact on microbiome composition and function, inflammation, and viral persistence, using longitudinal samples from 18 pig-tailed macaques. We will also test the mechanistic hypothesis that enhanced activity of gut sialidase, and/or increased expression of fucose-regulated bacterial virulence genes, contribute to SIV-associated microbial translocation. In Aim 1B, we will determine the impact of ART-treated HIV infection on the gut glycome, using cross-sectional samples from 40 HIV+ ART-suppressed individuals and well-matched HIV- controls. In Aim 2 and based on non-HIV studies demonstrating that sialidase inhibitor or L-fucose reduces microbial translocation and gut inflammation, we will test the hypothesis that treatment with sialidase inhibitor or L-fucose would reduce SIV-mediated microbial translocation and inflammation using SIV+ ART+ macaques. Our work aims to create a new paradigm, namely that host glycosylation is a key force that shapes the microbiome during ART-suppressed HIV infection. We propose that exploiting this mechanism will allow the design of novel strategies to manipulate these forces to reduce HIV persistence and/or prevent/delay the development of HIV-associated co-morbidities.